Oligomeric N-substituted glycines (NSG) and other "peptoids" are polymers that are well suited for the generation of diverse molecular libraries. These molecules can be prepared using conventional solid phase synthetic technologies that have been developed for the production of other polymers such as proteins. For example, methods are generally known for use in preparing defined polypeptides using Merrifield solid phase synthetic schemes. Merrifield (1963) J. Am. Chem. Soc. 85:2149-2154; Tam et al. (1987) The Peptides, Academic Press (New York), pp. 185-249. Another well-known method for achieving solid-phase peptide synthesis uses 9-fluorenylmethoxycarbonyl (Fmoc) protecting groups on the amino acids. Meienhofer et al. (1979) Int. J. Pept. Protein Res. 13:35, Atherton et al. (1979) Bioorg. Chem. 8:351. In this technique, the peptide is immobilized on any of a wide variety of commercially available polystyrene resins. Wang, S. (1973) J. Am. Chem. Soc. 95:1328, Mergler et al. (1988) Tetrahedron Lett. 29:4005, Albericio et al. (1987) Int. J. Pept. Protein Res. 30:206. The synthesis of individual peptoid oligomers can be carried out using equipment and techniques adapted from the above-referenced peptide syntheses. Simon et al. (1992) Proc. Natl. Acad. Sci. USA 89:9367.
Methods for the systematic synthesis of a multiplicity of polymers to screen for pharmacological or biological activity have also been developed. Particularly, combinatorial libraries can be prepared containing a large number of molecules using "resin-splitting" or "mix/split" techniques. Furka et al. (1991) Int. J. Peptide Protein Res. 37:487-493; Lam et al. (1991) Nature 354:82-84. Resin mixing/splitting methodology can also be used to generate peptoid libraries. Figliozzi et al. (1996) Methods in Enzymol. 267:437.
Although these methods of synthesis may be routine, they are quite laborious. The difficulty in conducting such syntheses becomes magnified when it is necessary to prepare many specified molecules in parallel, e.g., in the synthesis of combinatorial libraries. Accordingly, a number of automated systems for the synthesis of polypeptides and/or peptoid oligomers have been developed. One automated system described in Schnorrenberg et al. (1989) Tetrahedron 45:7759 relates to the synthesis of peptides on resin using several automated arms to withdraw solvent from a reaction vessel, add a solvent, wash and to mix reagents. Another automated system described in U.S. Pat. No. 5,240,680 to Zuckermann et al. relates to the synthesis of polypeptides using an apparatus having structure for automated transfer of reaction solutions into and out of a cleavage vessel, transfer of peptide solution from the cleavage vessel to the extraction vessel, and transfer of extraction solvent into and out of the extraction vessel. These automated systems have been modified (e.g., software modifications) for use in large scale peptoid syntheses.
The use of such automated systems in synthetic oligomer and polymer production schemes avoids a great deal of manipulation and increases the efficiency of synthetic polymer production. However, in the production of peptoids, a large amount of unused reagents are wasted in the synthetic processes, since such reagents are generally used iteratively and in excess (to increase reaction rate and overall yield) during the process.
Accordingly, there remains a need for a method and apparatus to synthesize peptoid oligomers using solid phase synthesis techniques, which avoids the waste associated with prior systems.